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United States Patent |
5,242,911
|
Bright
|
September 7, 1993
|
Bridged bicyclic imides as anxiolytics and antidepressants
Abstract
A series of bridged bicyclic imide compounds having a
4-(4-[2-pyrimidinyl]-1-piperazinyl)butyl group attached to the imide
nitrogen are useful for alleviating the symptoms of anxiety and depression
in human subjects.
Inventors:
|
Bright; Gene M. (Groton, CT)
|
Assignee:
|
Pfizer Inc. (New York, NY)
|
Appl. No.:
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355515 |
Filed:
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May 23, 1989 |
Current U.S. Class: |
514/183; 514/216; 514/256; 540/453; 540/461; 540/520; 544/230; 544/295 |
Intern'l Class: |
A61K 031/55; C07D 223/32 |
Field of Search: |
544/295,230
540/453,461,520
514/183,216,256
|
References Cited
U.S. Patent Documents
3717634 | Feb., 1973 | Wu et al. | 260/256.
|
3907801 | Sep., 1975 | Wu et al. | 260/268.
|
4006233 | Feb., 1977 | Shepard et al. | 424/251.
|
4173646 | Nov., 1979 | Shepard et al. | 424/270.
|
4182763 | Jan., 1980 | Casten et al. | 424/251.
|
4423049 | Dec., 1983 | Temple, Jr. | 424/251.
|
4507303 | May., 1985 | Ishizumi et al. | 514/255.
|
4543355 | Sep., 1985 | Ishizumi et al. | 514/253.
|
4562255 | Dec., 1985 | Freed et al. | 544/357.
|
4748240 | May., 1988 | Stack et al. | 544/47.
|
Other References
Chem. Abst. vol. 101, 1984, Abst. No. 23432K abstracting Korgeonkar et al.
J. Indian Soc. (1983) vol. 60, No. 9, pp. 874-876.
|
Primary Examiner: Bond; Robert T.
Attorney, Agent or Firm: Richardson; Peter C., Benson; Gregg C., Olson; A. Dean
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of pending application Ser. No.
312,772, filed Jun. 17, 1988 now abandoned claiming priority from PCT
International Application No. US86/02224, filed Oct. 21, 1986.
Claims
I claim:
1. A bridged bicyclic imide compound of the formula
##STR5##
and the pharmaceutically-acceptable acid-addition salts thereof, wherein
R.sup.1 and R.sup.2 are each selected from the group consisting of H and
CH.sub.3 ; and either
(a) X is selected from the group consisting of CH.sub.2, CH.sub.2 CH.sub.2
and CH.sub.2 CH.sub.2 CH.sub.2 ; and Y is selected from the group
consisting of CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, C(CH.sub.2).sub.4
and CH.sub.2 CH.sub.2 ;
or (b) X is selected from the group consisting of CH.dbd.CH, CH.sub.2
CH(CH.sub.3) and CH.sub.2 C(CH.sub.3).sub.2 ; and Y is CH.sub.2.
2. A compound according to claim 1 wherein X is selected from the group
consisting of CH.sub.2, CH.sub.2 CH.sub.2 and CH.sub.2 CH.sub.2 CH; and Y
is selected from the group consisting of CH.sub.2, CH(CH.sub.3),
C(CH.sub.3).sub.2, C(CH.sub.2).sub.4 and CH.sub.2 CH.sub.2.
3. A compound according to claim 2 wherein X is CH.sub.2 CH.sub.2.
4. A compound according to claim 3 wherein R.sup.1 and R.sup.2 are each H
and Y is CH.sub.2.
5. A compound according to claim 3 wherein R.sup.1 and R.sup.2 are each H
and Y is CH.sub.2 CH.sub.2.
6. A compound according to claim 3 wherein R.sup.1 is CH.sub.3, R.sup.2 is
H and Y is C(CH.sub.3).sub.2.
7. The dextrorotatory isomer of
3-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl)-1,
8,8-trimethyl-3-azabicyclo[3.2.1]octan-2,4-dione, a compound according to
claim 6.
8. A compound according to claim 1, wherein X is selected from the group
consisting of CH.dbd.CH, CH.sub.2 CH(CH.sub.3) and CH.sub.2
C(C.sub.3).sub.2 ; and Y is CH.sub.2.
9. A compound according to claim 8 wherein R.sup.1 and R.sup.2 are each H
and X is CH.sub.2 CH(CH.sub.3).
10. A method of alleviating the symptoms of anxiety in a human subject,
which comprises administering to said subject an effective
anxiety-alleviating amount of a bridged bicyclic imide compound according
to claim 1.
11. The method according to claim 10, wherein said bridged bicyclic imide
compound is
3-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl)-3-azabicyclo[3.2.1]octan-2,4-
dione.
12. The method according to claim 10, wherein said bridged bicyclic imide
compound is the dextrorotatory isomer of
3-(4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl)-1,
8,8-trimethyl-3-azabicyclo [3.2.1]octan-2,4-dione.
13. A method of alleviating the symptoms of depression in a human subject,
which comprises administering to said subject an effective
depression-alleviating amount of a bridged bicyclic imide compound
according to claim 1.
14. The method according to claim 13, wherein said bridged bicyclic imide
compound is
3-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl)-3-azabicyclo[3.2.1]-octan-2,4
-dione.
15. The method according to claim 13, wherein said bridged bicyclic imide
compound is the dextrorotatory isomer of
3-(4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl)-1,
8,8-trimethyl-3-azabicyclo[3.2.1-dione.
16. A pharmaceutical composition which comprises a
pharmaceutically-acceptable carrier and a bridged bicyclic imide compound
according to claim I, wherein the weight ratio of said carrier to said
compound according to claim 1 is in the range from 20:1 to 1:1.
Description
TECHNICAL FIELD
Anxiety and depression are common afflictions which adversely affect a
significant portion of the human population. Both anxiety and depression
can appear as either acute or chronic disease states, and in certain
subjects these disease states can co-exist.
It has been known for many hears that the symptoms of anxiety and
depression in human subjects can often be alleviated by the administration
of certain chemical substances. In this regard, compounds which are used
to treat anxiety are called antianxiety agents, or anxiolytics; while
compounds which are used to treat depression are normally termed
antidepressants.
In modern medical practiace, a widely-used class of anxiolytics is the
benzodiazepines, such as diazepam, and common antidepressants are the
so-called "tricyclics," such as imipramine. However, benzodiazepines also
have sedative properties in addition to their antianxiety properties.
Moreover, tricyclic antidepressants often exhibit undesirable
cardiovascular and anticholinergic side-effects.
Accordingly there is a need for new pharmacologic agents for the treatment
of anxiety and depression. In particular, there is a need for anxiolytic
agents which do not possess sedative effects; i.e., there is a need for
anxiolytics which exhibit selectivity of action.
BACKGROUND ART
Certain glutarimide and succinimide compounds, substituted on nitrogen by a
(4-aryl-1-piperazinyl)alkyl or (4-heteroaryl-1-piperazinyl)alkyl group,
and having tranquillizing, antianxiety and/or anti-emetic properties are
known from U.S. Pat. Nos. 3,717,634, 3,907,801, 4,182,763, 4,423,049,
4,507,303, 4,562,255 and 4,543,355. Korgaonka et al., J. Indian Chem.
Soc., 60, 874 (1983), disclosed a number of
N-(3-[4-aryl-1-piperazinyl]propyl)camphorimides, which are alleged to have
sedative properties in mice.
DISCLOSURE OF INVENTION
This invention relates to new chemical compounds which possess antianxiety
and antidepressant properties. More particularly, the compounds of this
invention are bridged bicyclic imide compounds of the formula
##STR1##
and the pharmaceutically-acceptable acid-addition salts thereof, wherein
R.sup.1 and R.sup.2 are each selected from the group consisting of H and
CH.sub.3 ; and either
(a) X is selected from the group consisting of CH.sub.2, CH.sub.2 CH.sub.2
and CH.sub.2 CH.sub.2 CH.sub.2 ; and Y is selected from the group
consisting of CH.sub.2,CH(CH.sub.3), C(CH.sub.3).sub.2,C(CH.sub.2).sub.4
and CH.sub.2 CH.sub.2 ;
or (b) X is selected from the group consisting of CH.dbd.CH, CH.sub.2
CH(CH.sub.3) and CH.sub.2 C(CH.sub.3).sub.2; and Y is CH.sub.2.
Accordingly, this invention provides: (i) the novel compounds of the
formula I and the pharmaceutically-acceptable acid-addition salts thereof;
(ii) a method of alleviating the symptoms of anxiety in a human subject
which comprises administering to said subject a compound of formula I or a
pharmaceutically-acceptable acid-addition salt thereof; (iii) a method of
alleviating the symptoms of depression in a human subject which comprises
administering to said subject a compound of formula I or a
pharmaceutically-acceptable acid-addition salt thereof; and (iv)
pharmaceutical compositions which comprise a pharmaceutically-acceptable
carrier and a compound of formula I or a pharmaceutically-acceptable
acid-addition salt thereof.
A preferred group of compounds of the formula I comprises those compounds
wherein X is CH.sub.2 CH.sub.2. Particularly preferred compounds within
this preferred group are those wherein R.sup.1 is methyl, R.sup.2 is
hydrogen and Y is C(CH.sub.3).sub.2. An especially preferred individual
compound of this invention is the dextrorotatory isomer of
3-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl)-1,8,
8-trimethyl-3-azabicyclo[3.2.1]octan-2,4-dione.
DETAILED DESCRIPTION
The compounds of this invention are the compounds of the formula I and
salts thereof. In one method according to the invention, the compounds of
the formula I are prepared by reaction of a cyclic anhydride of the
formula II with the requisite amine of the formula III.
##STR2##
wherein R.sup.1, R.sup.2, X and Y are as defined previously. The reaction
between the anhydride II and the amine III is commonly carried out by
heating substantially equimolar quantities of the two compounds at a
temperature from 90.degree. to 160.degree. C., until the reaction is
substantially complete. The two reactants are usually heated in a
reaction-inert solvent; however, in those cases in which one or both of
the reactants is molten at the reaction temperature, the two reactants can
be heated in the absence of solvent. A reaction-inert solvent is one in
which at least one of the reactants is soluble, and which does not
adversely interact with either of the starting reactants or the product of
the formula I. Typical reaction-inert solvents which can be used include
hydrocarbons, such as benzene, toluene, xylene and decalin, and the methyl
and ethyl ethers of ethylene glycol, propylene glycol and diethylene
glycol. Reaction between an anhydride of the formula II and an amine of
the formula III is normally carried out under substantially anhydrous
conditions.
Reaction between an anhydride of formula II and an amine of the formula III
proceeds more rapidly at high temperatures than lower temperatures, and it
proceeds more rapidly in the absence of solvent than when carried out in
solution. Thus, in a typical case, reaction of a compound of formula II
with a compound of formula III in a reaction-inert solvent at about
120.degree. C. commonly takes several hours, e.g., 12 to 30 hours.
However, reaction times of as little as about one hour are sufficient if
reaction temperatures of about 220.degree.-30.degree. C. are used.
If no solvent has been used, the compound of formula I is obtained
directly. When a reaction-inert solvent has been used, the compound of
formula I is usually recovered by solvent evaporation. A compound of
formula I can be purified by standard procedures, such as
recrystallization and/or chromatography.
The anhydrides of the formula II are normally prepared by dehydration of
the corresponding dicarboxylic acid of the formula IV:
##STR3##
wherein R.sup.1, R.sup.2, X and Y are as defined previously. This
dehydration is carried out under standard conditions, well-known for this
kind of transformation. For example, in a typical procedure, a
dicarboxylic acid of the formula IV is heated under reflux for a few
hours, e.g., two to four hours, in a large excess of acetic anhydride.
Removal of the volatile materials by evaporation in vacuo then affords the
anhydride of formula II.
The dicarboxylic acids of the formula IV are either known compounds, which
are prepared by the known procedures, or they are analogs of known
compounds, which are prepared by methods analogous to the known
procedures. Methods which are available for preparing dicarboxylic acids
of the formula IV include ozonolysis of an olefin of the formula V, nitric
acid oxidation of a ketone of the formula VI and permanganate or periodate
oxidation of a diketone of the formula VII. Each of these reactions is
carried out by methods well-known in the art.
##STR4##
For examples of preparations of specific dicarboxylic acids of the formula
IV (or lower-alkyl esters thereof, which can be converted into the acids
by conventional hydrolysis methods), consult: Journal of Organic
Chemistry, 31, 3438 (1969); Helvetica Chimica Acta, 53, 2156 (1970);
Journal of the American Chemical Society, 98, 1810 (1976); Journal of
Organic Chemistry, 44, 1923 (1979); Australian Journal of Chemistry, 34,
665 (1981); and Canadian Journal of Chemistry, 59, 2848 (1981).
The amines of the formula III are prepared by known methods. Consult: U.S.
Pat. No. 4,423,049.
The compounds of the formula I are basic, and they will form acid-addition
salts. All such salts are within the scope of this invention, although for
administration to a human subject it is necessary to use a
pharmaceutically-acceptable salt. The compounds of formula I contain more
than one basic center; consequently, acid-addition salts can incorporate
one or more molecules of a salt-forming acid. When more than one molecule
of salt-forming acid is incorporated, the anionic counter ions can be the
same or different. Acid-addition salts of a compound of the formula I are
prepared by conventional methods. In a typical procedure, a compound of
formula I is combined with a stoichiometric amount of an appropriate acid
in an inert solvent, which can be aqueous, partially aqueous or
non-aqueous. The salt is then recovered by solvent evaporation, by
filtration if the salt precipitates spontaneously, or by precipitation
using a non-solvent followed by filtration. Typical salts which can be
prepared include sulfate, hydrochloride, hydrobromide, nitrate, phosphate,
citrate, tartrate, pamoate, sulfosalicylate, methanesulfonate,
benzenesulfonate and 4-toluenesulfonate salts.
As indicated hereinbefore, the compounds of formula I, wherein R.sup.1,
R.sup.2, X and Y are as defined previously, and the
pharmaceutically-acceptable acid-addition salts thereof, are active as
antianxiety (anxiolytic) agents. This activity can be demonstrated and
measured using the well-known Vogel anti-conflict test. See further, Vogel
et al., Psychophamacologia, 21, 1 (1971). In a typical variation of the
Vogel anti-conflict test, groups of rats are deprived of water for 48
hours, and then they are presented with an opportunity to drink water from
an electrified spout. The number of times that the rats drink water (and
therefore also receive an electric shock) during a 10 minute period is
measured for rats which have been dosed with a test compound (treated
rats). This number is compared with the number obtained for control rats,
i.e., rats which have not received the test compound. An increase in the
number of times that treated rats drink water, over the number of times
that control rats drink water, is indicative of antianxiety activity in
the compound being tested.
The antianxiety activity of the compounds of the formula I, and the
pharmaceutically-acceptable acid-addition salts thereof, makes them useful
for administration to humans for alleviating the symptoms of anxiety.
The compounds of the formula I, and the pharmaceutically-acceptable
acid-addition salts thereof, have antidepressant properties.
Antidepressant activity can be measured in rats using well-known
procedures. See further, Porsolt et al., European Journal of Phamacology,
47, 379 (1978).
The antidepressant activity of the compounds of the formula I and the
pharmaceutically-acceptable acid-addition salts thereof, makes them useful
for administration to humans for alleviating the symptoms of depression.
A compound of formula I, or a pharmaceutically-acceptable salt thereof, can
be administered to a human subject either alone, or, preferably, in
combination with pharmaceutically-acceptable carriers or diluents, in a
pharmaceutical composition, according to standard pharmaceutical practice.
A compound can be administered orally or parenterally, which includes
intravenous and intramuscular administration. However, the preferred route
of administration is oral. Additionally, in a pharmaceutical composition
comprising a compound of formula I, or a pharmaceutically-acceptable salt
thereof, the weight ratio of carrier to active ingredient will normally be
in the range from 20:1 to 1:1, and preferably 10:1 to 1:1. However, in any
given case, the ratio chosen will depend on such factors as the solubility
of the active component, the dosage contemplated, and the precise dosage
regimen.
For oral use of a compound of this invention, the compound can be
administered, for example, in the form of tablets or capsules, or as an
aqueous solution or suspension. In the case of tablets for oral use,
carriers which can be used include lactose and corn starch, and
lubricating agents, such as magnesium stearate, can be added. For oral
administration in capsule form, useful diluents are lactose and dried corn
starch. When aqueous suspensions are required for oral use, the active
ingredient can be combined with emulsifying and suspending agents. If
desired, certain sweetening and/or flavoring agents can be added. For
intramuscular and intravenous use, sterile solutions of the active
ingredient can be prepared, and the pH of the solutions should be suitably
adjusted and buffered. For intravenous use, the total concentration of
solutes should be controlled to render the preparation isotonic.
When a compound of the present invention is to be used in a human subject,
the daily dosage will be determined by the prescribing physician. In
general, the dosage will depend on the age, weight and response of the
individual patient, as well as the severity of the patient's symptoms.
However, in most instances, an effective anxiety-alleviating amount and an
effective depression-alleviating amount of a compound of the formula I, or
a pharmaceutically-acceptable acid-addition salt thereof, will be from 1
to 300 mg per-day, and preferably 5 to 100 mg per day, in single or
divided doses. Naturally, the more active compounds of the invention will
be used at the lower doses, while the less active compounds will be used
at the higher doses. Also, for a given compound, an effective
depression-alleviating amount will usually be greater than an effective
anxiety-alleviating amount.
The following examples and preparations are being provided solely for
further illustration. For nuclear magnetic resonance spectra (NMR
spectra), absorptions are given in parts per million (ppm) downfield from
tetramethylsilane.
EXAMPLE 1
Dextrorotatory Isomer of 3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-1,8,
8-trimethyl-3-azabicyclo[3.2.1]octan-2,4-diode
A solution of 1.79 g (7.6 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 1.37 g (7.5 mmol) of
d-camphoric anhydride in 50 ml of xylene was heated under reflux for 22
hours with continuous removal of water (Dean-Stark trap). The resulting
solution was cooled and evaporated, and the residue was dissolved in 25 ml
of warm isopropanol. The solution was allowed to cool, and the solid which
appeared was recovered by filtration. This afforded 740 mg (25% yield) of
the title compound, mp 94.degree.-95.degree. C., [alpha].sup.20.sub.D
=+7.1.degree. (c=10; C.sub.2 H.sub.5 OH)
The .sup.1 H-NMR spectrum of the product (250 MHz; CDCl.sub.3) showed
absorptions at 8.24 (d,2H,J=4Hz), 6.41 (t,1H,J=4Hz), 3.76 (t,4H,J=4Hz),
3.63 (m,2H), 2.63 (d,1H), 2.40 (t,4H,J=4Hz), 2.31 (m,2H), 2.20-2.04
(m,2H), 1.94-1.74 (m,2H), 1.74-1.6 (m,2H), 1.54-1.3 (m,4H), 1.1 (s,3H) and
0.87 (m,6H) ppm.
The .sup.13 C-NMR spectrum (250 MHz; CDCl.sub.3) showed absorptions at
178.2, 176.2, 161.7, 157.6, 109.7, 58.3, 56.6, 54.4, 53.0, 44.1, 43.7,
39.1, 34.2, 25.7, 25.0, 24.3, 22.0, 19.3 and 14.1 ppm.
The high resolution mass spectrum showed a molecular ion at M.sup.+
=399.2616. C.sub.22 H.sub.33 N.sub.5 O.sub.2 : requires M.sup.+ =399.2637.
Analysis: Calcd. for C.sub.22 H.sub.33 N.sub.5 O.sub.2 : C,66.12; H,8.34;
N,17.53%. Found: C,65.91; H,8.47; N,17.47%.
EXAMPLE 2
Levorotatory Isomer of 3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-1,
8,8-trimethyl-3-azabicyclo[3.2.1]octan-2,4-dione
Following substantially the procedure of Example 1, 1.27 g (5.39 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine was reacted with 0.98 g (5.37
1-camphoric anhydride. The product was chromatographed on silica gel,
eluting with dichloromethane/methanol (95:5), to give 0.88 g (42% yield)
of the title compound. After recrystallization from isopropanol/hexane,
the product had mp 92.degree.-94.degree. C., [alpha].sup.20.sub.D
=7.4.degree. (c=10, C.sub.2 H.sub.5 OH).
The .sup.1 H-NMR and .sup.13 C-NMR spectra of the product were essentially
identical to those of the product of Example 1.
EXAMPLE 3
Racemic 3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-1,8,
8-trimethyl-3-azabicyclo[3.2.1]octan-2,4-dione
The title compound was prepared from 2.47 g (10.4 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 1.89 g (10.3 mmol) of
dl-camphoric anhydride, substantially according to the procedure of
Example 1. This afforded 0.7 g of product, mp 94.degree.-97.degree. C.
(17% yield).
The .sup.1 H-NMR and .sup.13 C-NMR spectra of the product were essentially
identical to those of the product of Example 1.
The high resolution mass spectrum showed a molecular ion at M.sup.+
=399.2669. C.sub.22 H.sub.33 N.sub.5 O.sub.2 requires M.sup.+ =399.2637.
EXAMPLE 4
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-3-azabicyclo[3.2.1]octan-2,4-d
ione
The title compound was prepared from 1.92 g (8.2 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 1.14 g (8.14 mmol) of
3-oxabicyclo[3.2.1]octan-2,4-dione, substantially following the procedure
of Example 1. Yield: 1.0 g (34% yield).
The .sup.1 H-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 8.02 (d,2H,J=4Hz), 6.20 (t,1H,J=4Hz), 3.56 (t,4H,J=4Hz),
3.40 (m,2H), 2.88 (m,2H), 2.22 (t,4H,J=4Hz), 2.12 (m,2H),1.96-1.74 (m,3H),
1.72-1.56 (m,2H), 1.48-1.3 (m,1H) and 1.3-1.1 (m,4H) ppm.
The .sup.13 C-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 176.2, 161.4, 157.5, 109.6, 58.0, 52.8, 44.6, 43.4, 38.3,
32.3, 27.0, 25.7 and 23.8 ppm.
The high resolution mass spectrum showed a molecular ion at M.sup.+
=357.2181. C.sub.19 H.sub.27 N.sub.5 O.sub.2 requires M.sup.+ =357.2167.
EXAMPLE 5
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]-butyl)-3-azabicyclo[3.3.1]nonan-2,4-
dione
Following substantially the procedure of Example 1, 2.78 g (11.8 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 1.88 g
(12.2 mmol) of 3-oxabicyclo[3.3.1]nonan-2,4-dione. The product was
chromatographed on silica gel, eluting with dichloromethane/methanol
(90:10), to give 2.04 g (47% yield) of the title compound.
The .sup.1 H-NMR spectrum of the product (250 MHz; CDCl.sub.3) showed
absorptions at 8.25 (d,2H,J=4Hz), 6.42 (t,1H,J=4Hz), 3.88-3.68 (m,6H),
2.86-2.76 (m,2H), 2.45 (t,4H,J=4Hz), 2.37 (m,2H), 2.2-2.07 (m,1H),
2.05-1.88 (m,2H) and 1.74-1.1 (9H,m) ppm.
The .sup.13 C-NMR spectrum of the product (250 MHz; CDCl.sub.3) showed
absorption at 175.5, 161.7, 157.7, 109.8, 58.3, 53.0, 43.5, 39.3, 38.5,
28.3, 26.2, 24.2 and 19.5 ppm.
The high resolution mass spectrum showed a molecular ion at M.sup.+
=371.2293. C.sub.20 H.sub.29 N.sub.5 O.sub.2 requires M.sup.+ =371.2324.
EXAMPLE 6
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)8,
8-dimethyl-3-azabicyclo[3.2.1]octan-2,4-dione
Following substantially the procedure of Example 1, 0.54 g (2.34 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 0.36 g
(2.14 mmol) of 8,8-dimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione. The
product was chromatographed on silica gel, eluting with
dichloromethane/methanol (96:4), to give 0.25 g (32% yield) of the title
compound.
The .sup.1 H-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 8.12 (d,2H,J=3Hz), 6.30 (t,1H,J=3Hz), 3.66 (t,4H,J=4Hz),
3.51 (m,2H), 2.50 (m,2H), 2.32 (t,4H,J=4Hz), 2.23 (m,2H), 2.16-2.02
(m,2H), 1.74-1.6 (m,2H), 1.37 (m,4H), 0.96 (s,3H) and 0.84 (s,3H) ppm.
The .sup.13 C-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 176.4, 157.6, 109.7, 58.2, 54.8, 53.0, 43.5, 42.0, 38.5,
26.4, 25.6, 24.1, 23.8 and 20.9 ppm.
The high resolution mass spectrum showed a molecular ion at M.sup.+
=385.2427. C.sub.21 H.sub.31 N.sub.5 O.sub.2 requires 385.2480.
EXAMPLE 7
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-1,
5-dimethyl-3-azabicyclo[3.2.1]octan-2,4-dione
Following substantially the procedure of Example 1, 4.2 g (17.8 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 2.99 g
(17.8 mmol) of 1,5-dimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione. The
product was chromatographed on silica gel, eluting with
dichloromethane/methanol (96:4), to give 1.4 g (21% yield) of the title
compound.
The .sup.1 H-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 8.01 (d,2H,J=4Hz), 6.20 (t,1H,J=4Hz), 3.57 (m,4H), 3.45
(m,2H), 2.22 (m,4H), 2.13 (m,2H), 1.70-1.54 (m,5H), 1.38-1.2 (m,5H) and
1.10 (s,6H) ppm.
The .sup.13 C-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 178.1, 161.4, 157.5, 109.6 58.1, 52.8, 49.0, 46.5, 43.4,
39.1, 35.8, 25.7, 23.9 and 20.3 ppm.
The high resolution mass spectrum showed a molecular ion at M.sup.+
=385.2484. C.sub.21 H.sub.31 N.sub.5 O.sub.2 requires M.sup.+ =385.2480.
EXAMPLE 8
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-3-azabicyclo[3.2.2]nonan-2,4-d
ione
An intimate mixture of 0.5 g (2.14 mmol) of
1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine and 0.22 g (1.42 mmol) of
3-oxabicyclo[3.2.2]nonan-2,4-dione was heated in an oil bath at
220.degree.-230.degree. C. for 15 minutes. An additional 0.22 g (1.42
mmol) of 3-oxabicyclo[3.2.2]nonan-2,4-dione was added. Heating in an oil
bath at 220.degree.-230.degree. C. was continued for 15 minutes and then
an additional 0.22 g (1.42 mmol) of 3-oxabicyclo[3.2.2]-nonan-2,4-dione
was added. Heating was continued for 30 minutes at 220.degree.-230.degree.
C. and then the reaction mixture was cooled. The resulting product was
chromatographed on silica gel, eluting with dichloromethane/methanol (96:4
followed by 94:6), to give 46 mg of the title compound (6% yield).
The .sup.1 H-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 8.26 (d,2H,J=4Hz), 6.46 (t,.sup.1 H,J=4Hz), 3.90
(t,4H,J=3Hz), 3.72 (t,2H,J=4Hz), 3.04 (m,2H), 2.68 (t,4H,J=3 Hz), 2.56
(t,2H,J=4Hz), 1.95-1.7 (m, 8H) and 1.64-1.42 (m,4H) ppm.
The .sup.13 C-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 178.9, 161.4, 157.7, 110.2 57.6, 52.2, 43.1, 42.4, 41.5,
25.8, 22.7 and 21.8 ppm.
The high resolution mass spectrum showed a molecular ion at M.sup.+
=371.2316. C.sub.20 H.sub.29 N.sub.5 O.sub.2 requires M.sup.+ =371.2323.
EXAMPLE 9
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-8-methyl-3-azabicyclo
[3.2.1]octan-2,4-dione can be prepared from
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and
8-methyl-3-oxabicyclo[3.2.1]octan-2,4-dione, substantially following the
procedure of Example 1.
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-8,8-tetramethylene-3-azabicycl
o [3.2.1]octan-2,4-dione can be prepared from
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and
8,8-tetramethylene-3-oxabicyclo[3.2.1]octan-2,4-dione, substantially
following the procedure of Example 1.
3-(4-[4-(4-Fluoro-2-pyrimidinyl)-1-piperazinyl]-butyl)-1,
8,8-trimethyl-3-azabicyclo[3.2.1]octan-2,4-dione can be prepared from
1-(4-aminobutyl)-4-(4-fluoro-2-pyrimidinyl)piperazine and
1,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione, substantially
according the procedure of Example 1.
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-3-azabicyclo[3.2.1]oct-6-en-2,
4-dione can be prepared from 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine
and 3-oxabicyclo[3.2.1]oct-6-en-2,4-dione, substantially following the
procedure of Example 1.
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-6-methyl-3-azabicyclo
[3.2.1]octan-2,4-dione can be prepared from
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and
6-methyl-3-oxabicyclo[3.2.1]octan-2,4-dione, substantially following the
procedure of Example 1.
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-6,6-dimethyl-3-azabicyclo
[3.2.1]octan-2,4-dione can be prepared from
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and
6,6-dimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione, substantially following
the procedure of Example 1.
3-(4-[4-(4-Fluoro-2-pyrimidinyl)-1-piperazinyl]-butyl)-3-azabicyclo
[3.2.1]oct-6en-2,4-dione can be prepared from
1-(4-aminobutyl)-4-(4-fluoro-2-pyrimidinyl) piperazine and
3-oxabicyclo[3.2.1]oct-6-en-2,4-dione, substantially following the
procedure of Example 1.
EXAMPLE 10
Mono-hydrochloride Salt of the Dextrorotatory
Isomer of
3-(4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl)-1,8,8-trimethyl-3-azabicyclo
[3.2.1]octan-2,4-dione
To a refluxing solution of 1.04 g (2.6 mmol) of the dextrorotatory isomer
of 3-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl)-1,
8,8-trimethyl-3-azabicyclo[3.2.1]-octan-2,4-dione in 5 ml of isopropanol
was added 0.55 ml (2.65 mmol) of 4.8N aqueous hydrochloric acid. The
resulting solution was allowed to cool to room temperature, and then the
volume was reduced to 3 ml by evaporation in vacuo. An additional 5 ml of
isopropanol was added and the solution was heated to the boiling point.
The solution was allowed to cool slowly, with stirring. The solid which
appeared was collected by filtration, to give 0.64 g (56% yield) of the
title salt, mp 207.degree.-08.degree. C.
The .sup.13 C-NMR spectrum (250 MHz; D.sub.2 O) showed absorptions at
182.4, 180.8, 161.3, 159.6, 113.0, 57.3, 55.7, 52.3, 45.4, 42.2, 39.4,
34.8, 25.8, 25.1, 22.04, 22.0, 19.3 and 14.3 ppm.
Analysis: Calcd. for C.sub.22 H.sub.33 N.sub.5 O.sub.2 .multidot.HCl: Cl,
8.13%. Found: Cl, 8.02%.
PREPARATION 1
3-Oxabicyclo[3.2.2]nonan-2,4-dione
A solution of 2.9 g of cis-cyclohexane-1,4-dicarboxylic acid in 25 ml of
acetic anhydride was heated under reflux for 2.5 hours. The solvent was
removed by evaporation in vacuo, and the residue was triturated under
diethyl ether several times. The residue was dried under high vacuum to
give 2.5 g (97% yield) of the title compound.
The .sup.13 C-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 170.5, 41.4 and 25.2 ppm.
The .sup.1 H-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 2.24-1.34 (m,8H) and 2.5 (m,2H) ppm.
PREPARATION 2
3-Oxabicyclo[3.2.1]octan-2,4-dione
A solution of 1.63 g of cis-cyclopentane-1,3-dicarboxylic acid in 8.2 ml of
acetic anhydride was heated in an oil bath at ca. 100.degree. C. for 45
minutes. The excess acetic anhydride and acetic acid were removed by
evaporation in vacuo to give a solid which was triturated under diethyl
ether. This afforded 1.14 g (79% yield) of the title anhydride.
The .sup.13 C-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 170.1, 41.8, 31.1 and 26.4 ppm.
The .sup.1 H-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 3.2 (M,2H), 2.36-1.9 (m,8H) and 1.82-1.66 (m,2H) ppm.
PREPARATION 3
1,8,8-Trimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione (1-Camphoric Anhydride)
The product of Preparation 5 was cyclized with acetic anhydride, using the
procedure of Preparation 2, to give 1.0 g (97% yield) of the title
compound.
PREPARATION 4
cis-Cyclohexane-1,4-dicarboxylic Acid
A steady stream of ozone was passed through a mixture of 15 g (0.14 mole)
of bicyclo[2.2.2]oct-2-ene and 300 ml of methanol at -70.degree. C. for 4
hours. The ozone stream was stopped, the mixture was allowed to warm to
room temperature, and then the solvent was removed by evaporation in
vacuo. The residue was dissolved in 72 ml of formic acid, and to the
resulting solution was added, cautiously, portionwise, 50 ml of 30%
hydrogen peroxide. The resulting mixture was heated to 70.degree. C., at
which point an exothermic reaction took place. After the exothermic
reaction had subsided, the reaction mixture was heated under reflux for 1
hour. Concentration of the reaction mixture in vacuo afforded a colorless
oil, which was partitioned between 300 ml of ethyl acetate and 300 ml of
water. The pH was adjusted to 9.5 using 2N sodium hydroxide. The aqueous
phase was removed, acidified to pH 2.0, and extracted with fresh ethyl
acetate. The ethyl acetate extract was dried (Na.sub.2 SO.sub.4) and
evaporated in vacuo. The residue was recrystallized from water to give 3.0
g (13% yield) of cis-cyclohexane-1,4-dicarboxylic acid.
The .sup.13 C-NMR spectrum of the product (300 MHz; CDCl.sub.3) showed
absorptions at 177.1, 39.8 and.25.2 ppm.
PREPARATION 5
1,2,2-Trimethyl-cis-cyclopentane-1,3-dicarboxylic Acid (1-Camphoric Acid)
A solution of 1.0 g (7.2 mmol) of 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ene
in 20 ml of methanol was to -75.degree. C., and a steady stream of ozone
was passed through the solution for 1 hour. Excess ozone was removed using
a stream of nitrogen, and then the reaction mixture was warmed to room
temperature and evaporated in vacuo. The residue was dissolved in 10 ml of
formic acid, and 5 ml of 30% hydrogen peroxide was added portionwise. The
reaction mixture was heated to ca. 75.degree. C., at which point an
exothermic reaction took place. After the exothermic reaction had
subsided, the resulting mixture was heated under reflux for 1.5 hours. The
cooled mixture was evaporated in vacuo to give 1.1 g (78% yield) of the
title compound.
PREPARATION 6
1,7,7-Trimethylbicyclo[2.2.1]hept-2-ene
1,7,7-Trimethylbicyclo[2.2.1]heptan-2-one (1-camphor) was converted into
its 4-toluenesulfonylhydrazone, which was then reacted with methyllithium
in ether, to give the title compound. The method used was that described
by Shapiro and Duncan, Organic Synthesis, Vol 51, pp 67-69, for the
conversion of racemic camphor into racemic
1,7,7-trimethylbicyclo[2.2.1]hept-2-ene.
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